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211616Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211616Orig1s000 RISK ASSESSMENT and RISK MITIGATION REVIEW(S) Division of Risk Management (DRM) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER) Application Type NDA Application Number 211616 and 211617 PDUFA Goal Date February 21, 2020 OSE RCM # 2019-402 and 404 Reviewer Name Mei-Yean Chen, Pharm.D. Team Leader Naomi Boston, Pharm.D. Division Director Cynthia LaCivita, Pharm.D. Review Completion Date February 14, 2020 Subject Evaluation of Need for a REMS Established Name Bempedoic acid and bempedoic acid/ezetimibe fixed dose combination (FDC) Trade Name Nexletol and Nexlizet Name of Applicant Esperion Theraputics, Inc. Therapeutic Class An adenosine triphosphate-citrate lyase inhibitor Formulation(s) Nexletol 180 mg tablet and Nexlizet (bempedoic acid 180 mg and ezetimibe 10 mg) Dosing Regimen Oral tablet once daily 1 Reference ID: 4561902 Table of Contents EXECUTIVE SUMMARY ......................................................................................................................................................... 3 1 Introduction ..................................................................................................................................................................... 3 2 Background ...................................................................................................................................................................... 3 2.1 Product Information ........................................................................................................................................... 3 2.2 Regulatory History............................................................................................................................................... 4 3 Therapeutic Context and Treatment Options .................................................................................................... 4 3.1 Description of the Medical Condition .......................................................................................................... 4 3.2 Description of Current Treatment Options ............................................................................................... 5 4 Benefit Assessment ....................................................................................................................................................... 6 5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 7 6 Expected Postmarket Use ........................................................................................................................................... 9 7 Risk Management Activities Proposed by the Applicant ............................................................................... 9 8 Discussion of Need for a REMS ................................................................................................................................. 9 9 Conclusion & Recommendations ........................................................................................................................... 10 10 Appendices ................................................................................................................................................................ 10 10.1 References ............................................................................................................................................................. 10 2 Reference ID: 4561902 EXECUTIVE SUMMARY This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity Nexletol/Nexlizet (bempedoic acid and bempedoic acid/ezetimibe) is necessary to ensure the benefits outweigh its risks. Esperion Therapeutics, Inc. submitted a New Drug Application (NDA 211616 and 211617) for bempedoic acid and bempedoic acid/ezetimibe with the proposed indication as an adjunct to diet and maximally tolerated statins therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of low-density lipoprotein cholesterol (LDL-C), with Limitations of Use: the effect of bempedoic acid on cardiovascular morbidity and mortality has not been determined. The risks associated with bempedoic acid include hyperuricemia and tendon rupture. The applicant did not submit a proposed REMS or risk management plan with this application. Division of Risk Management (DRM) has determined that a REMS is not needed to ensure the benefits of bempedoic acid outweigh its risks. Statin therapy sometimes is not enough to achieve appropriate lowering of LDL-C. There remains a clear need to develop a new therapy that is both effective and safe in lowering LDL-C. Although bempedoic acid effect in reducing LDL-C is modest, with its safety profile, it provides an additional therapeutic option in patients who are not able to meet goals with current available therapies. If the product is approved, the recommendations for monitoring signs and symptoms of hyperuricemia and tendon rupture will be communicated in the Warnings and Precautions section of the labeling. 1. INTRODUCTION This review evaluates whether a risk evaluation and mitigation strategy (REMS) for the new molecular entity (NME) bempedoic acid is necessary to ensure the benefits outweigh its risks. Esperion Therapeutics, Inc. (Esperion) submitted a New Drug Application (NDA) 211616 and 211617 for Nexletol and Nexlizet (bempedoic acid and bempedoic acid/ezetimibe) with the proposed indication as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFM) or established atherosclerotic cardiovascular disease (ASCVD) who require additional lowering of low-density lipoprotein cholesterol (LDL-C), with Limitations of Use: the effect of bempedoic acid on cardiovascular morbidity and mortality has not been determined. Nexlizet is a fixed dose combination (FDC), which contains bempedoic acid and ezetimibe (a cholesterol absorption inhibitor). This application is under review in the Division of Metabolism and Endocrinology Products (DMEP). The applicant did not submit a proposed REMS or risk management plan with this application. 2. BACKGROUND 2.1 PRODUCT INFORMATION Bempedoic Acid, a new molecular entity, is an adenosine triphosphate (ATP)-citrate lyase (ACL) inhibitor with the proposed indication as an adjunct to diet and maximally tolerated statins therapy for the treatment of adults with HeFM or established ASCVD who require additional lowering of LDL-C. As an 3 Reference ID: 4561902 ACL inhibitor, bempedoic acid acts upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase to inhibit cholesterol biosynthesis in the liver and lower LDL-C in blood via upregulation of LDL receptors. Bempedoic acid is available as a 180 mg tablet with the proposed dosing as one tablet orally once daily. Bempedoic Acid is not currently approved in any jurisdiction. 2.2 REGULATORY HISTORY The following is a summary of the regulatory history for NDA 211616 and NDA 211617 relevant to this review: x October 2009: Investigation New Drug (IND 106654) opened x August 2015: End of phase 2 (EOP2) meeting x September 2018: pre-NDA meeting x 02/20/2019: NDA 211616 submission received x 02/26/2019: NDA 211617 submission received x 08/15/2019: A Post Mid-cycle meeting was held between the Agency and the Applicant via teleconference. The Agency informed the Applicant that based on the currently available data, there were no safety issues that require a REMS for bempepoic acid. 3 THERAPEUTIC CONTEXT AND TREATMENT OPTIONS 3.1 DESCRIPTION OF THE MEDICAL CONDITION Familial hypercholesterolemia (FH) is the most common autosomal dominant genetic disease. The clinical syndrome is characterized by extremely elevated levels of LDL-C and a propensity to early onset of ASCVD. The American Heart Association criteria for clinical diagnosis of FH is LDL-C>190 mg/dL and either a first degree relative with LCL-C>190 mg/dL or with known premature coronary heart disease (<55 years men; <60 years women)1. The prevalence of FM varies on definition used and the population studied. Few patients in a general medicine practice have FH using a definition that includes genetic testing. FH is an autosomal dominant disorder inherited with a gene dosing effect, in which homozygotes are more adversely affected than heterozygotes. Homozygous FH patients are rare and have an estimated prevalence of about 1:300,000 to 1:400,000. LDL-C level in patients with homozygous FM usually is higher than 500 mg/dL, while LDL-C level in patients with heterozygous FH (HeFH) is around 200-550 mg/dL. HeFH is estimated to occur in about 1 in 300 individuals in Europe and 1 in 200- 250 individuals in the United States (US).2 HeFH patients have high LDL-C levels from birth and a higher risk of premature coronary heart disease. Individuals with HeFH often demonstrate tendon xanthomata if untreated and have a family history of hypercholesterolemia. The prevalence of xanthomata increases with age, eventually occurring in 75% of patients with HeFH. 4 Reference ID: 4561902 Cardiovascular disease (CVD) is the leading cause of death in the United States (US)a affecting over one third of Americans b.3 Heart attack and stroke are usually
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